Orosensory Contributions to Alcohol Ingestion

描述（由申请人提供）：本提案代表了酒精药理学和味觉神经生物学领域的研究人员之间的合作努力，以系统地检查味觉受体和处理食欲口服酒精信息的中枢神经回路对遗传介导的酒精偏好的贡献。尽管在确定介导酒精强化和促进其消耗的生物学机制方面取得了重大进展，但我们对控制口服酒精摄入开始和维持的复杂神经解剖回路的理解还远远不够。在过去十年中，来自动物和人类研究的大量证据支持酒精摄入与天然增强甜味物质摄入之间存在强大的遗传影响关系，但酒精和甜味摄入遗传共变异的机制目前尚不清楚。我们实验室最近的研究结果表明，口服酒精刺激可以有效地激活孤立束核中的甜味反应味觉回路，并且通过口服甜味受体的药物阻断可以直接抑制这些途径中酒精诱导的活性。新的初步行为数据表明，小鼠T1r3甜味受体的基因缺失在长期摄入酒精测试中对通常高度偏好的浓度产生了冷漠。具体目标1下的实验将测量多个选择性繁殖的酒精偏好/非偏好大鼠系及其非选择祖系在NST中对乙醇味觉信息的神经生理处理，以验证酒精诱导的中央甜味回路激活增强是一种与遗传介导的酒精偏好相关的一致生物表型的假设。具体目标2下的实验将检验味觉甜味受体阻断对酒精和甜味偏好的P、HAD1、HAD2和C57BL系/品系及其各自的非偏好/非选择系/品系对乙醇的心理生理口感觉反应的影响，以验证减少口服酒精刺激甜味通路将降低口感觉介导的乙醇偏好的假设。在本项目结束时，我们将产生一系列有价值的数据，以解决味觉受体和中枢神经通路传递食欲口服酒精信息对遗传影响的乙醇偏好的具体贡献。更广泛地说，这些研究将增强我们对中枢神经系统处理酒精感觉信息的理解，这一领域目前还没有得到很好的理解。

DESCRIPTION (provided by applicant): The present proposal represents a collaborative effort between investigators in the fields of alcohol pharmacology and gustatory neurobiology to systematically examine the contribution of gustatory receptor and central neural circuits processing appetitive oral alcohol information to genetically-mediated alcohol preference. Although significant progress has been made in identifying the biological mechanisms that mediate alcohol reinforcement and contribute to its consumption, our understanding of the complex neuroanatomical circuits that control initiation and maintenance of oral alcohol ingestion is far from complete. A substantial body of evidence from animal and human studies over the last decade has supported a robust genetically-influenced relationship between the ingestion of alcohol and consumption of naturally-reinforcing sweet substances, but the mechanisms underlying inherited co-variation in alcohol and sweet intake are presently unknown. Recent findings from our laboratory have shown that oral alcohol stimulation potently activates sweet-responsive gustatory circuits in the nucleus of the solitary tract and that alcohol-induced activity in these pathways is directly inhibited by pharmacological blockade of oral sweet receptors. New preliminary behavioral data indicate that genetic deletion of the T1r3 sweet taste receptor in mice produces indifference to alcohol in long-term intake tests at concentrations that are normally highly preferred. Experiments under Specific Aim 1 will measure the neurophysiological processing of ethanol gustatory information in the NST across multiple selectively bred alcohol-preferring/-nonpreferring rat lines and their nonselected progenitor lines to test the hypothesis that enhanced alcohol-induced activation of central sweet taste circuits is a consistent biological phenotype associated with genetically-mediated alcohol preference. Experiments under Specific Aim 2 will examine the effects of gustatory sweet receptor blockade on psychophysical orosensory responses to ethanol in alcohol- and sweet-preferring P, HAD1, HAD2, and C57BL lines/strains and their respective nonpreferring/nonselected lines to test the hypothesis that reduction of oral alcohol stimulation of sweet taste pathways will decrease orosensory-mediated ethanol preference. At the conclusion of this project, we will have produced a body of valuable data addressing the specific contribution of gustatory receptor and central neural pathways conveying appetitive oral alcohol information to genetically-influenced ethanol preference. More generally, these studies will enhance our understanding of the central nervous system processing of alcohol sensory information, an area that is currently not well understood.